Compositions and methods of treating skin fibrotic disorders

ABSTRACT

A method for preventing and/or modulating formation of a dermal fibrotic disorder includes administering a therapeutically effective amount of a multi-phase modulator to a subject in need thereof. The multi-phase modulator is selected from the group consisting of axitinib, nintedanib, sorafenib, sunitinib, lenvatinib, panatinib, pazopanib, regorafenib, and riociguat. The dermal fibrotic disorder is acne scars, skin scars such as keloids and hypertrophic scars, wrinkles, cellulite and dermal neoplastic fibrosis, scarring alopecia, various vasculopathy, vasculitis, burn wound healing, diabetic foot syndrome, scleroderma, arthrofibrosis, peyronie&#39;s disease, dupuytren&#39;s contracture, or adhesive capsulitis

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/767,137, filed on Apr. 9, 2018, (U.S. Publication No.2019-0070160 A1), which is a 371 application of PCT/US2016/055865, filedon Oct. 7, 2016, which claims the benefit of U.S. Provisional PatentApplication No. 62/238,309, filed on Oct. 7, 2015, the disclosure ofwhich is incorporated by reference in its entirety.

TECHNICAL FIELD

This invention relates to compositions and methods for preventing ortreating formation of fibrotic lesions, including skin scars such askeloids and hypertrophic scars.

BACKGROUND

Dermal wound healing involves several phases: hemostasis, inflammation,proliferation, and tissue maturation. The overall process is induced andregulated by a complex array of factors, such as growth factors andcytokines.

The initial hemostasis controls the release of a variety of growthfactors and/or cytokines from activated platelets to promote bloodclotting. The hemostasis phase is followed by the inflammation phase.

The inflammation phase induces vasodilation and results in an influx oflymphocytes and macrophages. Macrophages will release growth factors,such as platelet-derived growth factor (PDGF), fibroblast growth factor(FGF), transforming growth factor-β (TGF-β), vascular endothelial growthfactor (VEGF), interleukin-1 (IL-1), epidermal growth factor (EGF), andbasic fibroblast growth factor (bFGF) that stimulate fibroblasts cellsto promote the proliferation phase.

As the proliferative phase progresses, these growth factors stimulateangiogenesis and fibroplasias to rebuild blood flow to tissues afterinjury. Finally, the tissues mature to complete the wound healingprocesses. The tissue maturation phase also requires growth factors tocontrol cell differentiation.

Because the wound healing processes involve multiple phases that requiredifferent factors at different times, any improper action of thesefactors in any phase may result in improper wound healing. For example,excessive fibrosis may lead to undesirable scar formation.

Given these multiple factors and their spatial and temporalinteractions, identifying an appropriate drug treatment strategy ischallenging. For effective controls of dermal wound healing, a therapymay need to modulate more than one phase and target for a positive woundrepair outcome.

SUMMARY OF THE INVENTION

Embodiments of the present invention relate to compositions and methodsfor preventing and/or modulating the formation of dermal fibroticdisorders. Embodiments of the invention are based on therapeuticutilities of compounds possessing certain spectrum of pharmacologiceffects to modulate exuberant activities in various phases of woundhealing, thereby preventing and/or alleviating aberrant fibrotic tissueformations (e.g., scar formations). Specifically, compounds of theinvention include agents that can interfere with multiple phases(multiple targets) of wound healing processes. These agents will bereferred to as “multi-phase modulators” or “multi-target modulators.”The “multi-phase modulators” or “multi-target modulators” may includemultikinase inhibitors that can inhibit multiple kinases, as well assoluble guanylate cyclase (SGC) stimulators that can stimulate theactivities of soluble guanylate cyclase.

In one aspect, embodiments of the invention relate to methods forpreventing and/or modulating formation of a dermal fibrotic disorder. Amethod in accordance with embodiments of the invention includesadministering a therapeutically effective amount of a multi-phasemodulator to a subject in need thereof. The subject may be a mammal,particularly a human.

In accordance with embodiments of the invention, a multi-phase modulatormay be a multiple-kinase (“multikinase”) inhibitor or a solubleguanylate cyclase (SGC) stimulator (e.g., riociguat). As used herein,the term a “multikinase inhibitor” refers to a compound that can inhibitmultiple kinases, particularly multiple receptor tyrosine kinases. Asoluble guanylate cyclase (SGC) stimulator can stimulate the activity ofan SGC, leading to the formation of cyclic GMP (cGMP), which is a secondmessenger in various signal transduction pathways.

In accordance with embodiments of the invention, a multikinaseinhibitor, for example, may include axitinib, nintedanib, sorafenib,sunitinib or lenvatinib, which can inhibit receptor tyrosine kinases,such as VEGFR receptors (VEGFR-1, VEGFR-2, and/or VEGFR-3) and PDGFreceptors (PDGFR1 and/or PDGFR2). In addition, compounds of theinvention (e.g., axitinib, nintedanib, sorafenib, sunitinib, andlenvatinib) also have various degrees of inhibitory potencies againstfibroblast growth factor receptors (FGFR).

In accordance with embodiments of the invention, the multikinaseinhibitors may include, but are not limited to, axitinib, nintedanib,sorafenib, sunitinib, lenvatinib, panatinib, pazopanib, regorafenib, andtheir stereoisomer, tautomer, prodrug, free base, analogs, metabolites,pharmaceutically acceptable salt, solvate or solvate of a salt thereof.These compounds have anti-multikinase activities, such as anti-VEGFR,anti-PDGFR, and/or anti-FGFR activities. As shown in this description,these multikinase inhibitors can inhibit exuberant tissue fibrosis orscar formation. They are effective in remedying undesired scarformation, presumably due to their abilities to inhibit multiplekinases, such as receptor tyrosine kinases that mediate signaltransductions in the various phases of wound healing, thereby modulatingthe wound healing processes at multiple phases.

As used herein, a “pharmaceutically acceptable salt” refer to a compoundthat has been modified by adding an acid or base to make a salt thereof,wherein the compound may be a parent compound, or a prodrug, aderivative, a metabolite, or an analog of the parent compound.

In accordance with some embodiments of the invention, the multikinaseinhibitor is axitinib. Axitinib is a tyrosine kinase inhibitor ofVEGFR-1, VEGFR-2 and VEGFR-3. Axitinib has been shown to potentlyinhibit VEGF-mediated endothelial cell proliferation and survival.Axitinib also inhibits closely related receptor tyrosine kinases (RTKs),such as PDFGR-1, PDGFR-2, and KIT.

In accordance with some embodiments of the invention, the multikinaseinhibitor is nintedanib. Nintedanib is tyrosine kinase inhibitor ofvarious receptors, such as VEGFR, FGFR, PDGFR-α and PDGFR-β, and FGF.

In accordance with some embodiments of the invention, the multikinaseinhibitor is sorafenib. Sorafenib is a tyrosine kinase inhibitor ofseveral receptors, such as VEGFR-2, VEGFR-3 and PDGFR2

In accordance with some embodiments of the invention, the multikinaseinhibitor is sunitinib. Sunitinib is tyrosine kinase inhibitor of VEGFRand PDGFR.

In accordance with some embodiments of the invention, the multikinaseinhibitor is lenvatinib. Lenvatinib is a tyrosine kinase receptorinhibitor of various receptors, such as VEGFR-1, VEGFR-2, VEGFR-3,FGFR-1, FGFR-2, FGFR-3, FGFR-4, and PDGFR-α.

In accordance with some embodiments of the invention, the multi-phasemodulator is an SGC stimulator, such as riociguat. Riociguat, a solubleguanylate cyclase stimulator, may have effects on proliferation,fibrosis and inflammation in wound healing.

In accordance with embodiments of the invention, an agent forcontrolling exuberant activities in various phases of wound healing maybe used with other types of agents that can interfere with one or morephases involved in wound healing. These other agents may includeanti-angiogenic agents, anti-inflammatory agents, or anti-vascularpermeability agents. Preferred anti-angiogenic agents include, but arenot limited to, tyrosine kinase inhibitors, in particular, thosetargeting multiple receptors, such as those described in further detailherein: angiostatic cortisenes; matrix metalloprotease inhibitors;integrin inhibitors; PDGF antagonists; anti-proliferatives; hypoxiainducible factor-I inhibitors; fibroblast growth factor inhibitors;epidermal growth factor inhibitors; tissue inhibitor ofmetalloproteinases inhibitors; insulin-like growth factor inhibitors;tumor necrosis factor inhibitors; antisense oligonucleotides; anti-VEGFantibody, VEGF trap, anti-VEGF and/or anti-PDGF compounds, and theirstereoisomer, tautomer, prodrug, free base, analogs, metabolites,pharmaceutically acceptable salt, solvate or solvate of a salt thereof.

In accordance with embodiments of the invention, the dermal fibroticdisorders include but not limited to acne scars, skin scars such askeloids and hypertrophic scars, wrinkles, cellulite and dermalneoplastic fibrosis, scarring alopecia, various vasculopathy,vasculitis, burn wound healing, diabetic foot syndrome, scleroderma,arthrofibrosis, peyronie's disease, dupuytren's contracture, or adhesivecapsulitis.

In accordance with embodiments of the invention, compounds/molecules ofthe present invention may be administered by oral, parenteral, buccal,vaginal, rectal, inhalation, insufflation, sublingual, intramuscular,intradermal, subcutaneous, topical, intranasal, intraperitoneal,intrathoracic, intralesional, paralesional, intravenous, epidural,intrathecal, or intracerebroventricular routes, or by injection into thetissue and/or joints.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows TGF-β1 mRNA expression levels in wound sites treated withcompounds of the invention relative to those in an untreated unwoundedsite on the dorsum of pigs.

FIG. 2 shows images of pig dermal tissues from histologic slides afterhematoxylin and eosin staining. There was a decrease inneovascularization and fibrosis in drug treatment groups as compared tothe untreated wound control. Panel (A) unwounded normal skin. Panel (B)untreated wound tissue, showing more neovascularization and fibrosis.Panel (C) axitinib treated wound, showing neovascularization and reducedfibrosis.

FIG. 3 shows results of nintedanib (labeled as AIV002) treatment ofrabbit ear hypertrophic scar. Nintedanib treatment decreasedneovascularization and dermal fibrosis. Panel (A) shows H&E staining(left: untreated; right: treated wound), wherein the untreated site hassubstantial neovascularization (left), relative to the treated site(right). Panel (B) shows Mason's Trichrome staining (left: untreated;right treated wound).

DETAILED DESCRIPTION

Embodiments of the present invention relate to compositions (multi-phasemodulators) and methods for preventing and/or modulating the formationof dermal fibrotic disorders. Dermal wound healing involves severalphases: hemostasis, inflammation, proliferation, and tissue maturation.The overall process is induced and regulated by a complex array offactors, such as growth factors and cytokines. Effective approaches tothe control of exuberant activities in would healing likely requirecontrols and modulations in multiple phases.

Factors involved in wound healing exert their functions by binding totheir respective receptors to activate various signaling pathways. Thesereceptors include tyrosine kinases. Therefore, receptor tyrosine kinaseinhibitors (particularly multikinase inhibitors) can be used to regulatethe exuberant wound healing processes. Embodiments of the invention arebased on therapeutic utilities of compounds that possess a certainspectrum of pharmacologic effects to modulate exuberant activities invarious phases of wound healing, thereby preventing and/or alleviatingaberrant fibrotic tissue formations (e.g., scar formations).

Because various kinases are involved in different phases of the woundhealing processes, compounds of the invention include multikinaseinhibitors that can inhibit multiple kinases, thereby interfering withmultiple kinase-mediated signaling pathways. By inhibiting multiplekinases, one can achieve overall effects that may not be achievable byinhibiting a single kinase. In other words, by inhibiting multiplekinases in multiple phases of the wound healing processes, one may beable to achieve therapeutically effective effects to have a meaningfulcontrol of the undesirable fibrosis.

Compounds of the invention, for example, may include axitinib,nintedanib, sorafenib, sunitinib, lenvatinib, panatinib, pazopanib, andregorafenib, which can potently inhibit receptor tyrosine kinases, suchas VEGFR receptors (VEGFR-1, VEGFR-2, and/or VEGFR-3) and/or PDGFreceptors (PDGFR1 and/or PDGFR2). In addition, these compounds also havedifferent extents of inhibitory potencies against fibroblast growthfactor receptors (FGFR). Having the abilities to inhibit multiplereceptor tyrosine kinases (e.g., VEGFR, PDGFR, and/or FGFR), thesecompounds can produce effective controls of undesirable fibrosis, suchas in scar formation.

In addition to multikinase inhibitors, soluble guanylate cyclase (SGC)stimulators may also be used in embodiments of the invention. SGCstimulators may also interfere with multiple phases of wound healing.Thus, in accordance with some embodiments of the invention, a compoundof the invention may be an SGC stimulator, such as riociguat.

As used herein, the term “dermal fibrotic disorder” refers to exuberantactivities in various phases of wound healing that would result inaberrant fibrotic tissue formations (e.g., scar formations).

As used herein, the term a “therapeutic effective amount” is an amountthat would achieve the desired therapeutic effects. A therapeuticeffective amount would depend on the patient conditions, routes ofadministration, administration regimes etc. One skilled in the art wouldbe able to determine a therapeutic effective amount without inventiveefforts.

The following describes some specific examples to illustrate embodimentsof the invention. One skilled in the art would appreciate that theseexamples are for illustration only and other modifications andvariations are possible without departing from the scope of theinvention.

Experiment #1

Porcine skin resembles human skin in many aspects. Both species have arelatively thick epidermis, distinct rete pegs, dermal papillae, anddense elastic fibers in the dermis. Furthermore, unlike rodents andrabbits, porcine skin is adherent to the subcutaneous structures,similar to human skin. Because of these anatomical similarities andother parallelisms in wound healing, porcine models have emerged asimportant foundations for the study of pathophysiology and potentialtreatment paradigms for abnormal wound healing. It has also beenobserved in porcine full-thickness wound healing in Yucatan Minipigsthat the spatial and temporal expressions of TGF-β1, PDGF and VEGF weresimilar to the patterns for the growth factors described above.Therefore, the full-thickness excision models in Yucatan minipigs arethe models for human wound healing studies.

In this experiment, multiple full-thickness excision wounds were made tothe dorsum of Yucatan minipigs, and the wound sites were allowed tore-epithelialized adequately. At four weeks post-wound, the wound siteshad normal to pink vascularity and had pliability. Epidermal hyperplasiawas observed, as expected for regenerative responses in thefull-thickness wounds.

On Day 28 post-wound, a dose (e.g., 1%) of axitinib, nintedanib,riociguat, sorafenib, sunitinib, and/or lenvatinib was administered intothe dermal tissue at or around the wound sites, once every two weeks ontwo occasions. One wound site was left untreated as the control for eachpig. Please note that the particular parameters in this example are onlyfor illustration. One skilled in the art would appreciate that thedosages, administration methods, treatment regimen, and theadministration sites may be varied to achieve similar results.

On Day 59 post wound, the minipigs were sacrificed and dermal tissueswere collected for qualitative and quantitative evaluation usinghematoxylin and eosin, and Mason's Trichrome staining. Dermalfibroplasia was characterized by increased numbers of fibroblasts in thedermis suspended in variable amounts of collagen in wounds.

In addition, total mRNA was isolated from skin biopsies of the treatedwound sites and the untreated unwounded sites of the pigs. The mRNAsamples were used to prepare cDNA and analyzed via qRT-PCR. The TGF-β1expression levels were assessed using beta actin as a reference gene.

Transforming-growth-factor (TGF)-β expression, following inflammatoryresponses, results in increased production of extracellular matrix (ECM)components, as well as mesenchymal cell proliferation, migration, andaccumulation. Therefore, TGF-β has been found to induce fibrosisassociated with chronic phases of inflammatory diseases. As shown inFIG. 1, compounds of the invention significantly reduced the expressionlevels of TGF-β1, suggesting that compounds of the invention can be usedto control undesired fibrosis.

The histologic evaluation results, shown in Table 1, indicate that thesecompounds are effective in controlling the undesirable neovascular andfibrotic formation.

Among the various test compounds administered as two biweeklytreatments, axitinib and nintedanib noticeably reducedneovascularization with a corresponding reduced dermal fibroplasia, asassessed by histopathologic examinations of the treated wounds relativeto the untreated wound (Table. 1).

FIG. 2 shows exemplary hematoxylin and eosin stainings of pig dermaltissues from treated and untreated wound sites. Panel (A) show astaining from an unwounded skin as a control. Panel (B) shows a stainingof a sample from a wounded site without treatment with any compound ofthe invention. It is evident that the wounded tissue has substantialneovascularization and fibrosis. Panel (C) shows a staining of a samplefrom a wounded site treated with axitinib. Axitinib treatment results insignificantly reduced neovascularization and reduced fibrosis, ascompared with the untreated wound (see Panel (B)). These results clearlyshow that compounds of the invention are effective in reducingneovascularization and fibrosis at the wounded sites. As a result,compounds of the invention may be used to reduce undesired fibrosis,such as scar formation.

TABLE 1 Qualitative assessments of dermal fibroplasia andneovascularization at wound sites after two doses. (minimal = 1, mild =2, moderate = 3, marked = 4, and severe = 5) Individual Scores & AverageScores (bolded) Finding axitinib nintedanib riociguat sorafenibsunitinib lenvatinib untreated Fibroplasia; dermis 2, 2, 3 3, 2, 2 3, 2,3 3, 3, 3 3, 3, 2 3, 3, 3 3, 3, 4 (2.33) (2.33) (2.67) (3.00) (2.67)(3.00) (3.33) Neovascularization; 1, 2, 2 2, 2, 1 3, 2, 3 2, 2, 3 2, 3,2 2, 3, 2 3, 1, 3 dermis (1.67) (1.67) (2.67) (2.33) (2.33) (2.33)(2.33)

As shown in Table 2, compounds of the invention also resulted inreduction of TGF-β1 mRNA expression levels at the treated wounds, ascompared to the expression level in unwounded normal skin, suggestingthat compounds of the invention can be used to control the exuberantfibrosis. Among these compounds, axitinib, nintedanib, riociguat,sorafenib, and sunitinib are the most effective.

TABLE 2 TGF-β1 mRNA expression in Yucatan pig skin wound sites aftertreatments. TGF-β1 mRNA Expression Fold Relative to Untreated UnwoundedAnimal Duplicate Control Number Set axitinib nintedanib riociguatsorafenib sunitinib lenvatinib 7369 1 0.37 0.56 0.39 0.43 0.45 0.38 20.68 0.63 0.49 0.55 0.64 0.69 7370 1 0.78 0.87 0.8 0.89 1.86 2.02 2 0.890.70 0.60 0.84 0.50 2.27 7371 1 0.68 0.66 0.76 0.60 0.53 0.62 2 0.640.55 0.87 0.53 0.48 0.89

Experiment #2

In rabbits, wounds are created down to the bare cartilage on the ventralsurface of the ear using a dermal biopsy punch. Because these wounds donot heal by contraction, epithelialization is delayed and a raised scaris created. By both appearance and histological analysis, these scarsresemble human hypertrophic scars. In this established model, it wasshown that reduced TGF-β expression results in reduced scarring, whichis consistent with the current understanding of the pathogenesis ofexcessive scarring/dermal fibrosis. Furthermore, excessive angiogenesisand vascularization have been shown to result in pathologicalhypertrophic scar in this model. Thus, this rabbit model was also usedto assess the compounds of the invention.

Eight wounds were created on the ventral surface of the ears of each ofNew Zealand White rabbits using skin punch biopsies, and then the woundswere allowed to heal for approximately 2 weeks.

A dose (e.g., 1%) of axitinib, nintedanib, riociguat, sorafenib,sunitinib, and/or lenvatinib was administered into the dermal tissue,once every two weeks on two occasions. Again, the specific doses,treatment methods and schedules are for illustration only. One skilledin the art would appreciate that variations and modifications arepossible to achieve similar results.

On Day 42 post wound, the rabbits were sacrificed and dermal tissueswere collected for qualitative and quantitative evaluation usinghematoxylin and eosin and Mason's Trichrome staining. In addition,TGF-β1 mRNA expression levels were measured using qRT-PCR.

Histologic slides for hematoxylin and eosin stainings were prepared fromthe wound sites. Tissues were evaluated qualitatively for inflammation,neovascularization, granulation tissue, degrees of re-epithelialization,and degrees of scarring (avascular collagen).

As compared with untreated wound and the vehicle-treated wound, thewounds treated with nintedanib had much less neovascularization and lessscar tissues. As compared with the vehicle-treated wound, the mean TGFb1mRNA level was lower after intradermal treatment with nintedanib.

FIG. 3 shows results of nintedanib (labeled as AIV002) treatment ofrabbit ear hypertrophic scar. Nintedanib treatment decreasedneovascularization and dermal fibrosis. Panel (A) shows H&E staining(left: untreated; right: treated wound), wherein the untreated site hassubstantial neovascularization (left), relative to the treated site(right). Panel (B) shows Mason's Trichrome staining (left: untreated;right treated wound).

In addition to nintedanib, other compounds of the invention also havesimilar effects. For example, As compared with the untreated wound andthe vehicle-treated wound, the wounds treated with axitinib had lessneovascularization, less fibrosis, and less scar tissues. As comparedwith the vehicle-treated wound, the mean TGFb1 mRNA level was lowerafter intradermal treatment with axitinib.

As compared with untreated wound and the vehicle-treated wound, thewounds treated with riociguat had slightly decreased neovascularizationand fibrosis.

As compared with untreated wound and the vehicle-treated wound, thewounds treated with sorafenib had slightly increased neovascularization,and similar or decreased fibrosis. As compared with vehicle-treatedwound, the mean TGFb1 mRNA level was lower after intradermal treatmentwith sorafenib.

As compared with untreated wound and the vehicle-treated wound, thewounds treated with sunitinib had more neovascularization, and similarfibrosis. As compared with the vehicle-treated wound, the mean TGFb1mRNA level was lower after intradermal treatment with sunitinib.

As compared with untreated wound and the vehicle-treated wound,intradermal treatment with lenvatinib had similar neovascularization,fibrosis, and re-epithelialization. As compared with the vehicle-treatedwound, the mean TGFb1 mRNA level was lower after intradermal treatmentwith lenvatinib.

TABLE 3 TGF-β1 mRNA expression in rabbit ear wound sites afterintradermal treatments. Rabbit TGFB1 mRNA Expression Fold by TreatmentRelative to Untreated Wounded (mean ± SD) Group N axitinib nintedanibriociguat sorafenib sunitinib lenvatinib Normal skin 3 0.61 ± 0.15Untreated 7 1.00 (all rabbits) Treated 5 or 6 0.87 ± 0.28 0.73 ± 0.131.14 ± 0.14 0.87 ± 0.13 0.76 ± 0.23 0.66 ± 0.25 (each drug) Vehicle 1 or2 1.09 1.03 ± 0.19 1.01 ± 0.22 0.87 ± 0.20 1.26 ± 0.79 0.73 ± 0.09 (eachdrug)

While the invention has been described with respect to a limited numberof embodiments, those skilled in the art, having benefit of thisdisclosure, will appreciate that other embodiments can be devised whichdo not depart from the scope of the invention as disclosed herein.Accordingly, the scope of the invention should be limited only by theattached claims.

What is claimed is:
 1. A method for modulating formation of a dermalfibrotic disorder, comprising: administering to a subject atherapeutically effective amount of multi-kinase inhibitor selected fromthe group consisting of nintedanib, lenvatinib, or a combinationthereof; wherein the dermal fibrotic disorder is aberrant wound-healing,wrinkle, cellulite and dermal neoplastic fibrosis, vasculopathy,vasculitis, exuberant burn wound-healing, diabetic foot syndrome,arthrofibrosis, or Peyronie's disease.
 2. The method according to claim1, wherein the multi-kinase inhibitor is nintedanib.
 3. The methodaccording to claim 1, wherein the multi-kinase inhibitor is lenvatinib.4. The method according to claim 1, wherein the subject is a human. 5.The method according to claim 1, wherein the administering is byintramuscular injection, intradermal injection, intralesional injection,subcutaneous injection, topical application, localized administration orby injection into a joint.
 6. The method according to claim 1, whereinthe dermal fibrotic disorder is aberrant wound-healing.
 7. The methodaccording to claim 2, wherein the dermal fibrotic disorder is aberrantwound-healing.
 8. The method according to claim 3, wherein the dermalfibrotic disorder is aberrant wound-healing.
 9. The method according toclaim 1, wherein the dermal fibrotic disorder is wrinkle.
 10. The methodaccording to claim 1, wherein the dermal fibrotic disorder is celluliteand dermal neoplastic fibrosis.
 11. The method according to claim 1,wherein the dermal fibrotic disorder is vasculopathy.
 12. The methodaccording to claim 1, wherein the dermal fibrotic disorder isvasculitis.
 13. The method according to claim 1, wherein the dermalfibrotic disorder is exuberant burn wound-healing.
 14. The methodaccording to claim 1, wherein the dermal fibrotic disorder is diabeticfoot syndrome.
 15. The method according to claim 1, wherein the dermalfibrotic disorder is arthrofibrosis.
 16. The method according to claim1, wherein the dermal fibrotic disorder is Peyronie's disease.